Phosphorylation of C-terminal tyrosine residue 526 in FUS impairs its nuclear import

Simona Darovic, Sonja Prpar Mihevc, Vera Župunski, Gregor Gunčar, Maja Štalekar, Youn Bok Lee, Christopher E. Shaw, Boris Rogelj*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

Aberrant cytoplasmic aggregation of FUS, which is caused by mutations primarily in the C-terminal nuclear localisation signal, is associated with 3% of cases of familial amyotrophic lateral sclerosis (ALS). FUS aggregates are also pathognomonic for 10% of all frontotemporal lobar degeneration (FTLD) cases; however, these cases are not associated with mutations in the gene encoding FUS. This suggests that there are differences in the mechanisms that drive inclusion formation of FUS in ALS and FTLD. Here, we show that the C-terminal tyrosine residue at position 526 of FUS is crucial for normal nuclear import. This tyrosine is subjected to phosphorylation, which reduces interaction with transportin 1 and might consequentially affect the transport of FUS into the nucleus. Furthermore, we show that this phosphorylation can occur through the activity of the Src family of kinases. Our study implicates phosphorylation as an additional mechanism by which nuclear transport of FUS might be regulated and potentially perturbed in ALS and FTLD.

Original languageEnglish
Pages (from-to)4151-4159
Number of pages9
JournalJournal of Cell Science
Volume128
Issue number22
Early online date24 Sept 2015
DOIs
Publication statusE-pub ahead of print - 24 Sept 2015

Keywords

  • Amyotrophic lateral sclerosis
  • Frontotemporal lobar degeneration
  • FUS
  • Nuclear import
  • Phosphorylation
  • Transportin 1

Fingerprint

Dive into the research topics of 'Phosphorylation of C-terminal tyrosine residue 526 in FUS impairs its nuclear import'. Together they form a unique fingerprint.

Cite this